Abstract
Sudden infant death syndrome (SIDS) involves failure of arousal to potentially life threatening events, including hypoxia, during sleep. While neuronal dysfunction and abnormalities in neurotransmitter systems within the medulla oblongata have been implicated, the specific pathways associated with autonomic and cardiorespiratory failure are unknown. The neuropeptide substance P (SP) and its tachykinin neurokinin-1 receptor (NK1R) have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation, integration of cardiovascular control, and modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may therefore result in autonomic dysfunction during sleep and contribute to SIDS deaths. [125I] Bolton Hunter SP autoradiography was used to map the distribution and density of the SP, NK1R to 13 specific nuclei intimately related to cardiorespiratory function and autonomic control in the human infant medulla of 55 SIDS and 21 control (non-SIDS) infants. Compared to controls, SIDS cases exhibited a differential, abnormal developmental profile of the SP/NK1R system in the medulla. Furthermore the study revealed significantly decreased NK1R binding within key medullary nuclei in SIDS cases, principally in the nucleus tractus solitarii (NTS) and all three subdivisions of the inferior portion of the olivo-cerebellar complex; the principal inferior olivary complex (PIO), medial accessory olive (MAO) and dorsal accessory olive (DAO). Altered NK1R binding was significantly influenced by prematurity and male sex, which may explain the increased risk of SIDS in premature and male infants. Abnormal NK1R binding in these medullary nuclei may contribute to the defective interaction of critical medullary mechanisms with cerebellar sites, resulting in an inability of a SIDS infant to illicit appropriate respiratory and motor responses to life threatening challenges during sleep. These observations support the concept that abnormalities in a multi-neurotransmitter network within key nuclei of the medullary homeostatic system may underlie the pathogenesis of a subset of SIDS cases.
Highlights
Sudden infant death syndrome (SIDS) is a devastating and unexpected event in which a seemingly healthy infant dies in the first year of life during a sleep period, with no warning or prior indication of any adverse pathology to cause alarm [1]
post mortem interval (PMI) had no significant effect on neurokinin-1 receptor (NK1R) binding in any of the nuclei analyzed in either SIDS cases or nonSIDS controls and there were no significant differences in PMI between SIDS and controls (p = 0.244)
Taking the above observations together, we suggest that the significantly abnormal expression of NK1R in both the IO and nucleus tractus solitarii (NTS) in SIDS cases may contribute to an inability of a SIDS infant to execute appropriate motor responses in order to respond to life threatening challenges during sleep, which may underlie the pathogenesis of SIDS in conjunction with other neurotransmitter abnormalities within the same or associated medullary nuclei
Summary
SIDS is a devastating and unexpected event in which a seemingly healthy infant dies in the first year of life during a sleep period, with no warning or prior indication of any adverse pathology to cause alarm [1]. It is thought that SIDS or a certain subset of SIDS is caused by some form of underlying neural or systematic abnormality in medullary homeostatic control that impairs critical responses to life-threatening challenges such as hypoxia during a sleep period [1]. This failure is thought to result from abnormalities in a multi-neurotransmitter network of neural pathways in the medulla oblongata that control respiration, chemosensitivity, autonomic function and arousal. It is unlikely that dysfunction in only one neurotransmitter system exists given that the actions of neurochemicals are determined by the concurrent modulation and interaction with one another and any deficiencies in one will be immediately compensated by the action of others [12, 13]
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